I am a physician-scientist, now an Assistant Professor of Medicine in the Pulmonary Division at Stanford. My scientific interests lie in the study of protein-protein interactions involved in signalling. I am currently studying the process of T-cell activation, and its modulation by the immunosuppressive drugs cyclosporin A and FK506. This research has clinical relevance in guiding the rational design of better immunomodulators; on a basic level I investigate fundamental cell biology questions of intracellular signal transduction. The Research Career Development Award will allow me to establish myself as an independent investigator. In the immediate future I will continue my research on T-cell activation; in the long term I will address general questions of signal transduction, using lung tissues as model systems for neuroendocrine and cytokine signalling. The environment at Stanford is ideal: the hospital is committed to frontier research in transplantation biology and the basic science faculty is superb in immunology and molecular physiology. My current research focuses on two novel proteins that I have purified from the nucleus of activated T-cells that bind to enhancer sequences that regulate interleukin-2 gene transcription. These proteins, components of Nuclear Factor of Activated T-cells (NFAT), are transcriptional activators, and are regulated by post-translational modifications. I have cloned the cDNAs encoding these proteins; I will now study the structure and function of the proteins. By deletion mapping I will localize the DNA binding, dimerization and transactivation domains; by peptide mapping I will localize the sites of post- translational modifications that regulate function. I will identify the sites of modification sensitive to the immunosuppressive effects of cyclosporin A and FK506. These results will enhance our understanding of intracellular signalling processes and the regulation of immune function.